Roles of Carbon monoxide in regulation of sinusoidal blood flow and bile excretion

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This project aimed to examine whether carbon monoxide (CO), a product of heme oxygenase reaction, controls the contractility of bile canaliculus (BC) in hepatocytes and thus determine the ability of bile excretion in the liver. When BCs associated with the couplet cells in cultured rat hepatocyte suspension were observed using time-lapse video microscopy, they exhibited periodical contractions with most probable interval of 6 mm under our experimental conditions. Addition of 1 muM zinc protoporphyrin IX (ZnPP), a potent inhibitor of heme oxygenase, to the culture medium elicited a 40% shortening of the interval time together with an increase in intracellular calcium concentrations, while the same concentration of iron protoporphyrin IX did not induce such changes. The ZnPP-elicited increases in both contractile frequency and intracellular calcium concentrations were attenuated by the addition of 1 muM CO or 50 muM 1,2-bis(2-aininophenoxy) ethane-tetrraacetate, a calcium chelator Clotrimazole or metyrapone, inhibitors of cytochrome P450-dependent monooxygenase activities, also attenuated the ZnPP-induced elevation of the contractile frequency. On the other hand, intracellular cGM7P contents were not altered significantly by the application of ZnPP nor by CO, suggesting that the role of soluble guanylate cyclase is little, if any. These results indicate that CO generated by heme oxygenase controls the BC function by changing intracellular calcium concentrations presumably through a mechanism involving the cytochrome P450 reaction.